This R03 application extends the work proposed and completed in the parent K08, which established the necessity of the cytokines IL-4/IL-13 and TGF-?1 in experimental schistosomiasis-induced pulmonary hypertension. Schistosoma infection may be the most common cause of clinical WHO Group 1 pulmonary arterial hypertension (PAH) worldwide. In this proposal, our work broadens from investigating discrete cytokines to now seeking to understand the cells and regulators of cellular functions which contribute to the disease. Here, we propose to investigate the origins of the proximate Type 2 immune response which drives the pulmonary vascular disease, with the ultimate goal of uncovering targets for novel therapeutic interventions. Our hypothesis is that hypoxia inducible factor (HIF)-1? signaling in CD4+ T cells drives Schistosoma-PH. Our studies employ a novel mouse model of Schistosoma-PH, which we developed and validated in the context of the K08, and have now reported on in 9 publications to date. The relevance of our hypothesis to clinical disease is supported by our recent publication of increased IL-4/IL-13 signaling in human lung tissue of Schistosoma-PAH, and the complementary report of increased density of CD3+ T cells in this disease. Specific Aim 1 is to determine if CD4+ T cells are necessary for Schistosoma-PH. In Aim 1A, we will determine if B and T cells are necessary for Schistosoma-PH by analyzing the phenotype of doubly-deficient (Rag1-/-) mice sensitized and then challenged with S. mansoni eggs. In Aim 1B, we will determine if unstimulated, wildtype CD4+ T cells added to Rag1-/- mice are sufficient for PH to develop after Schistosoma sensitization and challenge. In Aim 1C, we will determine if activated Th2 CD4+ T cells from Schistosoma-sensitized mice are sufficient to convey adaptive immunity to Rag1-/- mice, thereby resulting in PH after intravenous egg challenge only. Specific Aim 2 is to determine if T cell HIF1? expression is necessary for Type 2 immunity effector function in Schistosoma- PH. In Aim 2A, we will determine if T cell HIF1? expression is necessary for Schistosoma?induced Type 2 immunity and PH, by determining the phenotype of HIF1?fl/fl x Lck-Cre mice (T cell-specific deficiency of HIF1?) sensitized and challenged with Schistosoma. In Aim 2B, we will determine if HIF1? in CD4+ T cells is necessary for these cells to produce IL-4 and IL-13, by adding CD4+ cells from HIF1?fl/fl x Lck-Cre mice to Rag1-/- mice, followed by Schistosoma sensitization and challenge. Our work, by analysis of a classic inducer of Type 2 immunity, the Schistosoma mansoni parasite, will contribute to understanding of the basic biology which drives this immune response. Our studies furthermore provide insights into other complications of parasitic diseases such as Schistosoma-induced hepatic fibrosis. By performing critical studies which tightly complement the parent K08, this R03 will facilitate the submission of a future R01 by the PI further investigating precise mechanisms which result in the Type 2 immune response, and how Type 2 immunity subsequently results in pulmonary hypertension.